Our group has been interested in glycosyltransferases such as GnT-III, GnT-IV, GnT-Va, Vb (GnT-IX), Fut8 and St6Gal1 and discovered several target proteins on which these enzymatic products carry (1). Core fucose, a product of α 1, 6 fucosyltransferase (Fut8), is a cancer biomarker target (1) and is also implicated in COPD (chronic obstructive lung disease), a progressive and inflammatory airway disease due to cigarette smoking and environmental chemicals. . We found that a keratan sulfate disaccharide designated L4 ([SO3--6]Galβ1-4[SO3--6] GlcNAc) showed protective effects in two murine COPD models. L4 attenuated alveolar destruction, reduced neutrophil influx and inflammatory cytokines, inactivated matrix metalloproteinase and myeloperoxidase in bronchoalveolar lavage fluid (2). We have also identified receptor protein of L4 and the underlying mechanism by which L4 suppresses inflammation.
Bisecting GlcNAc, a GnT-III product was high in Alzheimer’s disease patients (2). Analysis of knockout mice of GnT-III revealed that decreased cleavage of APP (Aβ-precursor protein) by BACE1 (β-site amyloid precursor protein cleaving enzyme-1) as well as decreased Aβ plaque. The lack of this modification directs BACE1 to late endosomes/lysosomes where it is less co-localized with APP, leading to accelerated lysosomal degradation.
GnT-Va producesb1,6 GlcNAc structure is known to play a key role in EMT (epithelial to mesenchaymal transition) and cancer metastasis due to modification of adhesion molecules such as E-cadherin and integrins. . Recently crystal of GnT-Va was obtained and bi-substrate analogue of GnT-Va is a good inhibitor for Gnt-V.
In conclusion new findings of various glycosyltransferase functions will open a new avenue toward novel and promising druggable candidates.